Adenosine is a naturally occurring purine nucleoside that is ubiquitous in mammalian cell types. Adenosine exerts its biological effects by interacting with A1, A2 (further subclassified as A2A and A2B) and A3 cell surface receptors, which modulate important physiological processes.
The A1 and A2A receptor subtypes are believed to play complementary roles in adenosine's regulation of a cell's energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and locally activates the A1 receptor to decrease the oxygen demand or activates the A2A receptor to increase the oxygen supply, thereby reinstating the balance of energy supply and demand within the tissue. The combined action of A1 and A2 subtypes increases the amount of available oxygen to tissue and protects cells against damage caused by a short-term imbalance of oxygen. One of the important functions of endogenous adenosine is to prevent tissue damage during traumas such as hypoxia, an ischemic condition, hypotension and seizure activity.
In addition, modulation of A2A receptors also regulates coronary vasodilation and A2A agonists are known to down-regulate the production of multiple inflammatory mediators and are beneficial in various animal models of inflammation.
Adenosine is also a neuromodulator, which modulates molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischemia and seizures. Neurotransmitters are ultimately responsible for neural degeneration and neural death, which can cause brain damage or death. Adenosine is thought to be an endogenous anticonvulsant agent that inhibits glutamate release from excitory neurons and neuronal firing. Adenosine agonists, therefore, are useful as antiepileptic agents.
Adenosine plays an important role as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischemia and hypoxia and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus are useful as cardioprotective agents.
Adenosine A2B receptors are ubiquitous and regulate multiple biological activities. A2B receptors have been implicated in mast-cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion. For example, adenosine binds to A2B receptors on endothelial cells and stimulates angiogenesis. Adenosine also regulates the growth of smooth muscle cell populations in blood vessels and stimulates A2B receptors on mast cells, thus modulating Type I hypersensitivity reactions. In addition, Adenosine stimulates gastrosecretory activity by ligation with A2B in the intestine.
In vitro studies have shown that adenosine receptor agonists promote the migration of endothelial cells and fibroblasts, and adenosine receptor agonists have proven to be useful to treat wounds and promote wound healing.
Adenosine A3 receptors modulate cell proliferation processes. See Bradley et al., J. Pharmacl. Expe.l Ther. 2001, 299:748-52.
International Publication No. WO 95/02604 discloses A3 adenosine receptor agonists and their use as locomotor depressants, hypotensive agents, anxiolytic agents, cerebroprotectants and antiseizure agents. U.S. Pat. No. 5,443,836 to Downey et al., discloses the use of adenosine A3 agonists for preventing ischemic heart damage. International Publication Nos. WO 98/50047 and WO 99/20284 also relate to ischemic protection.
International Publication No. WO 01/19360 discloses the use of A3 agonists to induce G-CSF secretion, induce proliferation or differentiation of bone marrow or white blood cells, treat or prevent leukopenia, treat or prevent toxic side effects of certain drugs, inhibit abnormal cell growth, and treat cancer.
International Publication No. WO 01/083152 discloses the use of adenosine A3 receptor agonists to activate natural killer (NK) cells.
International Publication No. WO 02/055085 discloses the use of adenosine A3 agonists to inhibit viral replication.
For a review of recent developments in the field of adenosine receptor agonists, see C. E. Muller, “Adenosine Receptor Ligands-Recent Developments Part I. Agonists,”in Current Medicinal Chemistry 2000, 7:1269-1288.
2-(N′-Alkylidenehydrazino)adenosines and their 5′-S-alkyl-5′-thio derivatives are reported in U.S. Pat. No. 5,278,150 to Olsson et al.; International Publication No. WO 9602553 to Di Ayres; Niiya et al. J. Med. Chem. 35:4557-4561 (1992); Niiya et al., J. Med. Chem. 35:4562-4566 (1992); Maget et al., Eur. J. Med. Chem. 30:15-25 (1995); Viziano et al., J. Med. Chem. 38:3581-3585 (1995); and Tilburg et al., J. Med. Chem. 45:420-429 (2002).
2-Cyanoadenosine derivatives are reported in Nair et al., J. Am. Chem. Soc. 111:8502-8504 (1989) and Ohno et al., Bioorg. Med. Chem., 12:2995-3007 (2004).
2-Cyano-6-substituted purines are disclosed in U.S. Pat. No. 5,219,840 to Gadient et al.; U.S. Pat. No. 6,448,236 to Monaghan; U.S. Pat. No. 6,638,914 to Fishman et al.; U.S. Pat. No. 6,921,753 to Mandell et al.; U.S. Patent Publication No. US 2002/0032168 to Mantell et al.; and U.S. Patent Publication No. US 2002/0058641 to Mantell et al.
2-Aminosubstituted adenosines and their 5′-amide derivatives are reported in Francis et al., J. Med. Chem. 34:2570-2579 (1991); Hutchison et al., J. Med. Chem. 33:1919-1924 (1990); U.S. Pat. No. 4,968,697 to Hutchison et al.; U.S. Pat. No. 5,280,015 to Jacobsen et al.; and U.S. Pat. No. 6,368,573 to Leung et al.
2-Alkylideneadenosines, 2-Alkyleneadenosines and 5′-carboxamides thereof are reported in Cristalli et al., J. Med. Chem. 38:1462-1472 (1995); Cristalli et al., J. Med. Chem. 37:1720-1726 (1994); Homma et al., J. Med. Chem. 35:2881-2890 (1992); Matsuda et al., J. Med. Chem. 35:241-252 (1992); Rieger et al., J. Med. Chem. 44:531-539 (2001); Beraldi et al., J. Med. Chem. 41:3174-3185 (1998); Vittori et al., J. Med. Chem. 39:4211-4217; U.S. Pat. No. 6,531,457 to Linden et al.; and U.S. Pat. No. 6,180,615 to Zablocki et al.
2-Chloro and 5′-substituted adenosines are disclosed in U.S. Pat. No. 5,589,467 to Lau et al.
2-Pyrazole and thiophene derivatives are disclosed in U.S. Pat. No. 6,403,567 to Zablocki et al.; U.S. Pat. No. 6,214,807 to Zablocki et al.; and U.S. Pat. No. 6,440,948 to Zablocki et al.
2-Carboxamides and aminomethyleneadenosine derivatives are disclosed in U.S. Pat. No. 6,525,032 to Mantell et al.; U.S. Patent Publication No. US 2002/0032168 to Mantell et al.; and U.S. Patent Publication No. US 2002/0058641 to Mantell et al.
2-Alkyl and aminoalkyl adenosine are disclosed in U.S. Pat. No. 6,326,359 to Monaghan et al.; U.S. Pat. No. 6,448,236 to Monaghan et al.; and U.S. Patent Publication No. US 2003/0013675 to Yeadon et al.
2-Thioether nucleosides are reported in U.S. Patent Publication No. US 2001/0051612 to Cristalli.
2-Aminoalkyl and 5′-heterocyclic nucleosides are disclosed in U.S. Pat. No. 6,426,337 to Cox et al.; U.S. Pat. No. 6,534,486 to Allen et al.; and U.S. Pat. No. 6,528,494 to Cox et al.
2-Alkoxyadenosines are reported in U.S. Pat. No. 5,140,015 to Olsson et al.
3′-Aminoadenosine derivatives are reported as highly selective A3 agonists in DiNinno et al., J. Med. Chem., 46:353-355, (2003); and U.S. Patent Publication No. 2003/0055021 to DeNinno et al.
Non-adenosine adenosine A2B receptor agonists are reported in Beukers et al., J. Med. Chem., 47:3707-3709 (2004).
The citation of any reference in Section 2 of this application is not an admission that the reference is prior art to this application.